Methacholine Chloride

Provocholine, used in a methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma. Provocholine, a cholinergic agonist used in a methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma (1)

• For inhalation solution: 100 mg of methacholine chloride crystalline powder, white to off-white in color in amber glass vials (powder is reconstituted and then diluted prior to administration)
• Inhalation solution ready-to-use (sterile): Contain the following strengths of methacholine chloride in a clear, colorless solution. i. 3 mL base solution (contains no methacholine chloride) ii. 0.0625 mg/mL (0.1875 mg/ 3 mL) of methacholine chloride iii. 0.25 mg/mL (0.75 mg/ 3 mL) of methacholine chloride iv. 1 mg/mL (3 mg/ 3 mL) of methacholine chloride v. 4 mg/mL (12 mg/ 3 mL) of methacholine chloride vi. 16 mg/mL (48 mg/ 3 mL) of methacholine chloride
• Inhalation solution (in a single-dose vial): 16 mg/mL (48 mg/ 3 mL) of methacholine chloride in a clear, colorless solution in a 3 mL plastic single-dose vial with a twist-off cap.
• For inhalation solution: 100 mg of methacholine chloride powder in amber glass vial (3)
• Inhalation solutions: o Ready-to-use-kit: base solution (contains no methacholine chloride), 0.0625 mg/mL (0.1875 mg/3 mL), 0.25 mg/mL (0.75 mg/3 mL), 1 mg/mL (3 mg/ 3mL), 4 mg/mL (12 mg/3 mL), and 16 mg/mL (48 mg/3 mL) of methacholine chloride (3) o Single-dose vial: 16 mg/mL (48 mg/3 mL) of methacholine chloride (3) —————————–

Provocholine is contraindicated in patients with: Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. Baseline FEV 1 < 60% predicted (adults or pediatric patients) or <1.5 L (adults) hypersensitivity to methacholine chloride or other parasympathomimetic agents (4) Baseline FEV 1 <60% predicted (adults or pediatric patients) or <1.5 L (adults) (4)

. Risk of Severe Bronchoconstriction: Severe bronchoconstriction can result from Provocholine administration. Do not use Provocholine in pediatric and adult patients with baseline FEV1 <60% predicted or adults with FEV1 <1.5 L. Not recommended in patients with clinically apparent asthma or wheezing. If severe bronchoconstriction occurs, reverse with administration of rapid-acting inhaled β2-agonist. (5.1)

• Bronchoconstriction from Inadvertent Exposure: Healthcare provider and any other personnel involved in the administration of the methacholine challenge test should take precautions to avoid inadvertent inhalation of Provocholine powder and nebulized aerosol (5.2)
• Risk in Patients with Coexisting Diseases and Conditions: Provocholine not recommended for patients with uncontrolled hypertension, aortic aneurysm, or history of myocardial infarction or stroke diseases. Consider the benefits and potential risk for use of Provocholine in patients with conditions that could be adversely affected by a cholinergic agent. (5.3)

5.1 Risk of Severe Bronchoconstriction Severe bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV 1 < 60% predicted or adults with FEV 1 < 1.5 L. Emergency equipment and medication should be immediately available to treat acute respiratory distress. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended. If severe bronchoconstriction occurs, reverse immediately by the administration of a rapid-acting inhaled β-agonist. If baseline spirometry is not performed or is measured inaccurately, the initial FEV 1 may be underestimated. In this situation, decreases in FEV 1 may not be detected after escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increase in the risk for excessive bronchoconstriction.

5.2 Bronchoconstriction from Inadvertent Exposure to Healthcare Providers Administering Provocholine The supplied Provocholine powder or the Provocholine nebulized aerosol may cause bronchoconstriction in healthcare providers administering Provocholine in a methacholine challenge test. Healthcare providers and any other personnel involved in the administration of Provocholine should take the following precautionary steps: Do not inhale the supplied Provocholine powder Do not handle the Provocholine powder if you have asthma or hay fever. Apply a low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air

5.3 Risk in Patients with Coexisting Diseases and Conditions Provocholine is not recommended for patients with uncontrolled hypertension, aortic aneurysm, or history of myocardial infarction or stroke diseases. Patients with epilepsy, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should undergo methacholine challenge only if the healthcare practitioner considers the benefit to the individual outweighs the potential risks.

The following adverse reactions associated with the use of Provocholine were identified in clinical studies or post marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory System: Bronchospasm (includes symptoms such as chest tightness, cough or wheezing). Less Common Adverse Reactions: Headache, throat irritation, light-headedness and itching. Adverse reactions are bronchoconstriction, headache, throat irritation, light-headedness, and itching (6) To report SUSPECTED ADVERSE REACTIONS, contact Methapharm at 1-866-701-4636 or call FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch

Beta-Adrenergic Blockers The use of beta-adrenergic blockers may impair reversal of Provocholine-caused bronchoconstriction. Beta-Agonists, Anticholinergics, and Theophylline Beta-agonists, anticholinergics, and theophylline inhibit the response of airways to Provocholine; therefore, hold these drugs before Provocholine use for the following duration:

• Short-acting β-agonists (e.g., albuterol): 6 hours
• Long-acting β-agonists (e.g., salmeterol): 36 hours
• Short-acting anti-cholinergics (e.g., ipratropium): 12 hours
• Long-acting anti-cholinergics (e.g., tiotropium): ≥168 hours
• Oral theophylline: 12-48 hours Oral or Inhaled Corticosteroids, and Inhaled Cromoglycate Regular use of oral or inhaled corticosteroids and inhaled cromoglycate may acutely decrease bronchial responsiveness to Provocholine. However, these drugs may be continued with Provocholine use. Beta-Adrenergic Blockers : May impair reversal of Provocholine-caused bronchoconstriction (7) Beta-Agonists, Anticholinergics, and Theophylline : Inhibit response to Provocholine; therefore, hold these drugs prior to Provocholine use (7) Oral or Inhaled Corticosteroids, and Inhaled Cromyoglycate : May decrease response to Provocholine (7)

. Pregnancy: Provocholine is not recommended (8.1)

8.1 Pregnancy Risk Summary The available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating effects of methacholine chloride on embryofetal development have not been conducted. Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended for pregnant women because of the potential for hypoxia in the fetus. If bronchial airway hyperreactivity is suspected, consider trial of empiric treatment. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation Risk Summary There are no available data on the presence of methacholine chloride in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of Provocholine used in a methacholine challenge test, has been established for the diagnosis of bronchial airway hyperreactivity in pediatric patients 5 years of age and older who do not have clinically apparent asthma. The safety and effectiveness of Provocholine have not been established in pediatric patients younger than 5 years of age.

8.5 Geriatric Use The diagnosis of bronchial airway hyperreactivity is largely performed in pediatric and younger adult patients. Clinical studies of Provocholine did not include patients 65 years of age or older.

Methacholine chloride is a cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Methacholine chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction.